Carcinomas of the gastrointestinal tract are a leading cause of cancer deaths in the United States. Colorectal and pancreatic cancer are estimated to constitute over 75% of all gastrointestinal tract cancers diagnosed in 1992. See generally Boring et al., Cancer J. Clin. 42:19 (1992).
As with other types of cancer, attempts have been made to control gastrointestinal cancer with chemotherapeutics. 5-Fluorouracil has been the agent most widely used in the treatment of these types of tumors. See J. S. Macdonald et al., Cancer 144:42 (1979).
Success with chemotherapeutics as anticancer agents generally has been hampered by the phenomenon of multiple drug resistance, resistance to a wide range of structurally unrelated cytotoxic anticancer compounds. J. H. Gerlach et al., Cancer Surveys 5:25 (1986). The underlying cause of progressive drug resistance may be due to a small population of drug-resistant cells within the tumor (e.g., mutant cells) at the time of diagnosis. J. H. Goldie and A. J. Coldman, Cancer Research, 44:3643 (1984). Treating such a tumor with a single drug first may result in a remission, where the tumor shrinks in size as a result of the killing of the predominant drug-sensitive cells. With the drug-sensitive cells gone, the remaining drug-resistant cells continue to multiply and eventually dominate the cell population of the tumor.
It is now known that drug resistance is due to a membrane transport protein, "P-glycoprotein," that can confer general drug resistance. M. M. Gottesman and I. Pastan, Trends in Pharmacological Science, 9:54 (1988). Phenotypically, over time, the tumor cells show a reduced cellular accumulation of all drugs.
The problem of drug resistance is no less significant in attempts to treat colon cancer with 5-fluorouracil. Indeed, metastases from the primary colon/rectal tumor are particularly resistant to this drug, leading many to conclude that secondary colon cancer (e.g., liver metastases) cannot be cured. K. Fischerman et al., Scand. J. Gastroent. Suppl. 37:111 (1976).
Use of 5-fluorouracil derivatives also has complications; in many cases, tumors that are resistant to 5-fluorouracil are also resistant to 5-fluorouracil analogues. H. Anai et al., Oncology 45:144 (1988). Furthermore, 5-fluorouracil and its derivatives have significant inherent toxicity. They do not specifically eliminate cancer cells; rather, they affect all replicating cells of the body.
What is needed is an approach to gastrointestinal cancer that is reliably tumoricidal. Importantly, the treatment must be effective with minimal host toxicity.